氟化氯[salophene]铁(III)络合物（salophene = N,N'-双(水杨基)-1,2-苯二胺）是有前途的抗癌剂。细胞凋亡和坏死诱导已被描述为其作用模式的一部分。然而，正如其他氯化[salophene]铁(III)复合物所证实的那样，铁死亡在细胞死亡诱导中的作用尚未得到研究。此外，细胞摄取这些化合物的机制尚不清楚。因此，在水杨基部分 (C1-C4) 的 3、4、5 或 6 位具有氟取代基的荧光氯代[salophene]铁 (III) 复合物的生物活性在恶性和非恶性细胞系中进行了重点评估研究转铁蛋白受体-1（TfR-1）参与细胞摄取、复合物对线粒体功能的影响以及细胞死亡的分子机制分析。所有复合物均显着降低了测试的卵巢癌（A2780、A2780cis）、乳腺癌（MDA-MB 231）和白血病（HL-60）细胞系的代谢活性，而非恶性人基质细胞系 HS-5 在一定浓度下的代谢活性显着降低。 0.5 μM 的浓度（代表大多数使用的致瘤细胞系中复合物的 IC50）不受影响。线粒体功能受损，表现为线粒体膜电位 ΔΨm 降低和线粒体活性降低。除了细胞凋亡和坏死性凋亡之外，铁死亡也被确定为作用模式的一部分。首次进一步证明，氟化氯[salophene]铁(III)复合物可下调TfR-1表达，与铁他汀II（一种通过TfR-1降解发挥作用的铁转运抑制剂）相当。 FerroOrange 染色进一步表明，复合物强烈增加细胞内铁 (II) 水平，作为诱导铁死亡的驱动力。总之，这些氟化氯[salophene]铁(III)复合物是有效的肿瘤细胞特异性化疗剂，具有治疗各种类型癌症的潜力。© 2024 作者。由美国化学会出版。

Fluorinated chlorido[salophene]iron(III) complexes (salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) are promising anticancer agents. Apoptosis and necrosis induction have already been described as part of their mode of action. However, the involvement of ferroptosis in cell death induction, as confirmed for other chlorido[salophene]iron(III) complexes, has not yet been investigated. Furthermore, the mechanism of cellular uptake of these compounds is unknown. Therefore, the biological activity of the fluorescent chlorido[salophene]iron(III) complexes with a fluorine substituent at positions 3, 4, 5, or 6 at the salicylidene moieties (C1-C4) was evaluated in malignant and nonmalignant cell lines with focus on the involvement of the transferrin receptor-1 (TfR-1) in cellular uptake, the influence of the complexes on mitochondrial function, and the analysis of the molecular mechanism of cell death. All complexes significantly decreased the metabolic activity in the tested ovarian cancer (A2780, A2780cis), breast cancer (MDA-MB 231), and leukemia (HL-60) cell lines, while the nonmalignant human stroma cell line HS-5 at a concentration of 0.5 μM, which represents the IC50 of the complexes in most of the used tumorigenic cell lines, was not affected. The mitochondrial function was impaired, as evidenced by a reduced mitochondrial membrane potential ΔΨm and decreased mitochondrial activity. Besides apoptosis and necroptosis, ferroptosis was identified as part of the mode of action. It was further demonstrated for the first time that fluorinated chlorido[salophene]iron(III) complexes downregulate TfR-1 expression, comparable to ferristatin II, an iron transport inhibitor that acts via TfR-1 degradation. FerroOrange staining further indicated that the complexes strongly increased the intracellular iron(II) level as a driving force to induce ferroptosis. In conclusion, these fluorinated chlorido[salophene]iron(III) complexes are potent, tumor cell-specific chemotherapeutic agents, with the potential to treat various types of cancers.© 2024 The Authors. Published by American Chemical Society.